Project Summary/Abstract: Target Validation Core (Core 3) With the explosion of new technologies, biomedical research has been moving at a very fast pace in generating novel links and suggesting promising therapeutic avenues. The research proposed in the MTDD COBRE application is expected to identify a number of exciting molecular targets. However, before further efforts and resources are devoted to these targets, it is crucial to have validation for physiological relevance and functional significance. With the common goal of achieving target validation, we propose to establish two key resources at UNMC, the Genome Editing facility and the Mouse Model and Imaging facility. Together, these facilities will comprise the Nebraska Center for Molecular Target Discovery and Development Target Validation Core. The newly developed genomic editing technology, CRISPR, allows researchers to examine the relevance of their target proteins or processes in a clean genetic background within a significantly shorter time frame. As we have accumulated extensive experience in the CRISPR technology, we propose to establish a core facility to provide the MTDD researchers with knockout or knockin cell lines for their genes of interest, thus allowing them to validate their findings in a reliable and efficient fashion. Another essential component of target validation is to determine the effect(s) of novel genetic, pharmacological, and environmental interventions on patient outcome. Mouse orthotopic xenograft models are ideal systems for the initial assessment of the impact of clinical interventions on disease outcome. To support the studies proposed in the MTDD COBRE application, we propose a core facility, which will focus on mouse models and feature state-of-art, advanced imaging capabilities to detect and monitor tumor development and progression non-invasively and effectively. Investigators with access to this core service will thus be better poised to understand the functional impact of specific genetic and pharmacologic interventions. Additional core strengths will include mouse metabolic assessment (by indirect calorimetry). The Core co-leaders have many years of experience in the field. Core staff are highly trained. We propose to ensure rigorous core quality at both an experimental (operator training and formalized equipment maintenance) and a systematic (input resulting from an annual external advisory board meeting) level. Together, the Target Validation Core is expected to provide the necessary technical input in target validation, and support MTDD investigators in achieving their goal of conducting high-impact research.